This K02 Independent Scientist Award for Dr. Neale will enable him to expand and refocus his methodological efforts in psychiatric genetic epidemiology. From a background of developing software (the Mx package) to fit models to data from twins and families, the candidate will obtain further training in the areas of molecular genetics and clinical psychiatry. Skills in these areas will enhance the quality and increase the breadth of models that will be applied to datasets collected at MCV. These data include twin-family studies of adult female and male twins in Virginia, of schizophrenia in Ireland (PI Dr. K. Kendler), and of school-age twins in Virginia and North Carolina (PI Dr. L. Eaves). Specific foci for model development and application include: (I) models for comorbidity that use information on age at onset in relatives as well as familial comorbidity patterns to distinguish between alternative hypotheses; (ii) methods to control for variable age at onset in genetic studies of populations still at risk; (iii) environmental moderation of genetic risk; (iv) relapse and remission over time; (v) combination of information from multiple informants; (vi) the resolution of genetic heterogeneity and its relationship to psychiatric nosology; and (vi) the integration of data from genetic markers to partition genetic factors into those from specific quantitative trait loci and those from background polygenic variation. These models will be developed and tested with simulated data. They will be applied to data on generalized anxiety disorder, major depression, panic disorder, alcohol abuse/dependence, and schizophrenia in adults, and conduct disorder and attention deficit/hyperactivity disorder in the school-aged twins.